Despite improvements in vaccine design, manufacture, and distribution, influenza A infection remains a significant public health concern. The February 2013 CDC Interim Adjusted Estimates of Seasonal Influenza Vaccine Effectiveness reported overall vaccine effectiveness of 56% and 67% against influenza A and B infections, respectively, with much reduced effectiveness of 9% observed for 65+ elderly, an at-risk population for respiratory complications. Of note, the report reinforces the need for continued advances in influenza vaccines, especially to increase protective benefits for older adults and notes, this season...antiviral treatment of elderly adults is especially important...preferably within 48 hours after illness onset... This past season's apparent mediocre protection against seasonal influenza also reemphasizes the threat of emergence of highly pathogenic pandemic strains as well as the potential use of influenza as a vehicle for biological warfare. Currently available direct acting antivirals for influenza infection remain vulnerable to the development of virus resistance. The present project proposes to validate a paradigm-shifting antiviral mechanism-of-action, the simultaneous modulation of specific host-encoded Sirtuins. Sirtuins are NAD+-dependent deacetylases more generally known for their role in the observed life-span increasing effects of caloric restriction and the red wine ingredien, resveratrol. Preliminary evidence for this grant proposal demonstrates that pharmacological Sirtuin modulation with tool compounds and proprietary hits from a completed sirtuin-modulator high- throughput screen, effectively blocks the growth of multiple human pathogenic viruses in culture, including influenza A. In fact, consistent with described mechanisms of Sirtuins as regulators of metabolism in the literature that can induce apoptosis specifically in metabolically-changed tumor but not normal cells, Sirtuin modulation appears to efficiently clear virus infection by specific apoptotic elimination of virally-infected cells while leaving uninfected cells intact i culture. Proposed SBIR Phase 1 goals are to validate proprietary chemical scaffolds identified in the screen and to validate Sirtuin modulation as an efficient host-targeted pan- influenza antiviral mechanism with demonstrated window of therapy in vivo as well as a reduced acquired- resistance profile compared to existing influenza antivirals. The observed viral clearance is remarkable and may in fact result in symptomatic improvements well beyond an early window of administration (48 hours in infected patients) to be tested in downstream SBIR Phase 2 using preclinical models predictive of the human condition. An initial target patient population, could in fact comprise older adults with poor immune response to vaccines, but in any case, the proposed host-targeted antivirals are predicted to complement existing vaccine and antivirals in pan-influenza effectiveness and acquired-resistance profile.